Circular peptide therapeutics for AML

Acute myeloid leukemia (AML) has an aggressive clinical course and a high mortality. It is driven by leukemic stem cells with a very heterogeneous mutation background, resulting in different subtypes. The properties of leukemic stem cells (e.g. epigenetic pattern, signaling) differ from those of the bulk AML population, making these cells difficult to eliminate. The standard of care for patients has changed only minimally over the past forty years and there is an urgent need for patient-tailored treatment options. Previous studies and preliminary data from us suggest that plant-derived circular peptides might be novel possible treatment options for AML. We now plan to explore these properties in detail and to define circular peptide drug candidate(s) for the precise treatment of specific AML subtypes. To do so we will take the advantage of our previously reported innovative murine hematopoietic progenitor cell model (HPCLSK) to mimic AML subtypes. These cells are able to re-feed the entire hematopoietic cell pool and if transformed induce disease in vivo. This system allows us to perform screening assays and mechanistic elucidation with infrequent progenitor cell populations which would usually need a high number of mice. In this study we propose to use different AML HPCLSK cells to elucidate the effectivity of the cyclotide T20K for AML. In addition we will determine novel peptides by screening a compound library of circular peptides derived from an ipecac root and violet plant extract. To get a deeper mechanistic insight which signaling pathways are targeted by the peptides we will perform transcriptome analysis of our defined top hits for each individual AML subgroup.We aim to find novel natural product-based treatment options for specific stem cell fractions in AML and to explore novel drug combinations with circular peptides.

Fonds der Stadt Wien für innovative interdisziplinäre Krebsforschung (MA 40)

Zentrum für Biologische Wissenschaften